PROTECT: on-line adaptive proton therapy for cervical cancer to reduce the impact on morbidity and the immune system

Rationale:
The current standard treatment for locally advanced cervical cancer is external
beam radiotherapy (EBRT) with concurrent chemotherapy followed by MRI-guided
intracavitary/interstitial brachytherapy. This combination of treatment
modalities is very effective for locoregional control. As most patients have
the prospect of long-term survival, they will also have to live with
treatment-related morbidity. This has substantial impact on many domains of
their life (physical, sexual, emotional, social, economic). Since most patients
are diagnosed in their early decades (peak incidence: 35-45 yrs), morbidity has
a major societal impact as well.
Severe late morbidity (grade 3-4) which requires medical intervention (grade 3)
and/or can be life-threatening (grade 4), occurs in 8-11% of patients and
concerns most often the gastro-intestinal and urogenital tract and, less
frequently, insufficiency fractures of the pelvic bones in the irradiated area.
Moreover, the number and functioning of circulating leukocytes (myeloid cells
and lymphocytes) can be reduced by pelvic radiotherapy, which might reduce
efficacy and feasibility of adjuvant chemo/immunotherapy.
Radiotherapy-related morbidity is a result of the dose to organs at risk (OAR)
and is both dose and volume dependent. With proton therapy (PT), OAR dose can
be further reduced by highly localized dose-deposition using its finite range.
The biggest dose reductions are observed in low-dose regions, such as bowel and
bone(marrow). For treatments that included both the pelvic and para-aortic
regions the dosimetric advantage of PT is even bigger.
This clinical study will be the first prospective comparative trial to directly
compare adaptive photon therapy (IMRT/VMAT) with adaptive PT (IMPT) on
dosimetric parameters and clinical outcomes. All participating patients will
undergo the current state-of-the-art treatment for LACC (primary chemoradiation
with concurrent cisplatin followed by image-guided adaptive brachytherapy).
With this study design we will create a homogenous population wherein only the
type of EBRT (IMRT/VMAT or IMPT) is different. Such a study will yield a wealth
of information on differences in the effects on dose-volume parameters and both
short-term and long-term morbidities. Moreover, it creates a unique opportunity
to study the effects of both types of EBRT on local and systemic immune
response.

Hypothesis:
I. Daily adaptive IMPT for locally advanced cervical cancer is clinically
feasible and will be able to spare the organs at risk to a significantly
greater extent than photon-based IMRT/VMAT, while maintaining coverage of the
target volume.
II. There are subgroups of patients with locally advanced cervical cancer that
will have a clinically relevant reduction of acute and late bowel morbidity if
treated with IMPT instead of IMRT/VMAT
III. With IMPT the suppression of the number of circulating leukocytes (myeloid
cells and lymphocytes) will be lower compared to IMRT/VMAT

Primary objective:
- To determine the difference in mean dose (Gy) to pelvic bones (whole pelvic
contour), and the difference in the mean V15Gy-bowelbag volume in cc (according
to EMBRACE bowel bag definition) between photon and proton therapy in clinical
practice.

Secondary objectives:
- Compare (IMRT/VMAT) photon with Proton Therapy (IMPT) on:
o Dosimetric parameters (target volumes and organs at risk)
o Clinical outcomes (response after 3 months, overall survival, pelvic- and
distant recurrence-free survival)
o Health-related quality of life (EORTC QLQC30 and EORTC QLQCX24/EN24)
o Safety & tolerability, grade >=2 according to NCI-CTCAE version 5.0
- Determine the effect of IMPT and IMRT/VMAT on the immune system and possible
differences, as measured by the number and function of circulating leukocytes
(myeloid cells and lymphocytes).
- Evaluation of bone marrow activity using the MRI Dixon sequence.

Multicentre, prospective, clinical, non-randomised phase 2 trial to compare
photon and proton therapy in patients with locally advanced cervical cancer who
are treated with pelvic +/-peri-aortic adaptive radiotherapy combined with
concurrent chemotherapy with curative intent.

The patient extra burden will be limited to two additional blood samples (61.5
mL, 8 and 12 weeks after treatment) and one additional tumour biopsy under
anaesthesia at first brachytherapy session. Additional blood samples (54 ml)
for immunomonitoring will be added to the standard of care blood drawing
(7.5mL) at baseline, week 4 of treatment, 4 weeks and 12 months after
treatment. The total volume of blood sampling will be 7.5 mL + 54 mL = 61.5 mL.
An additional blood sample can cause discomfort or hematoma. The extra biopsy
will be done when patient is already under general or spinal anaesthesia and
can cause, although rarely, complications such as bleeding and infection.
Furthermore, an extra MRI sequence (Dixon) will be added to the MRI at
baseline, brachytherapy and at 12 weeks and 12 months after treatment. The MRI
at these timepoints is already standard of care and will take approximately 5
minutes longer with this addition sequence. It is not standard of care to
always perform a MRI 12 months after treatment, but this is very frequently
done in the clinical setting. According to EMBRACE protocol (both LUMC and EMC
participate in this trial) a MRI after 12 months is part of the standard follow
up procedures. In daily practice, most women will have either a MRI, CT or
PET-CT scan at 12 months after treatment.
An optional second MRI (only Dixon sequence) at baseline before start of
treatment is encouraged but not mandatory.
Patients who will be treated with IMPT in the second, experimental phase of the
trial may have longer travel time to the HPTC and an extra intake session.
Although proceeding to the second phase of trial will not occur before the
technical aspects of optimal PT delivery have been optimized and implemented,
and whereas IMPT is already used for other tumour sites, the treatment with
IMPT for cervical cancer has not been performed yet in Holland PTC.
The benefit of participating in this study for all participating women is the
satisfaction of participating in a trial in order to improve the standard of
care for future cervical cancer patients. For the women who will be treated
with IMPT there is the potential benefit of being treated with a more precise
type of radiation therapy, with less radiation dose to the surrounding healthy
organs and thereby possibly reducing the risk of acute and late bowel
morbidity.
Filling in the quality of life questionnaires takes approximately 10-15 minutes
and women will be asked to return these questionnaires at baseline, week 4 of
treatment, end of treatment and 3-6-9-12 months after treatment. If women also
participate in the EMBRACE trial (same questionnaire at the same timepoints)
they can consent to use the same questionnaire for the two trials.